Prior art, for example, U.S. Pat. Nos. 3,081,225 and 3,256,150 are concerned with methods of orally administering to the afflicted, medicaments which are susceptible to attack by gastric acids. In these references, considerable stress is laid on the teaching that the combination of the enzyme, pregastric esterase and non-fat dry milk powder should be finally ground. It is clearly taught for administration as a powder, or as a powder to be encapsulated.
There is no suggestion in the prior art of a lipase enclosed in a selected matrix which will disintegrate in the intestinal portion of a mammalian G. I. tract. It is doubtful that dry fat milk solids with their high lactose content would offer protection to a drug which was sensitive to attack by gastric juices since lactose is highly soluble in water and acidic solutions.
U.S. Pat. No. 3,065,142 describes a gastric resistant pancreatin, a derivative of mammalian pancreas tissue containing a medicinal preparation, exemplified by a mixture of enzymes. However, this patent has a central teaching of treating the resulting mixture of medicinal agent and gastric resistant material with heat to liquify the gastric resistant material. The ultimate form of the preparation is granules, rather than tablets, substantially resistant to gastric disintegration. The present invention does not rely on a means which protects the sensitive medicinal agent by requiring utilization of heat to achieve the necessary intermixing.
Another reference of interest is the Italian journal Il Farmaco, Vol. 22, p. 585, 1967 (Oct.). Therein the authors suggest the use of whole powdered skim milk to protect the activity of pancreatic enzymes. However, this material is also certainly subject to attack because of its high percentage of water-soluble lactose.
It is, therefore, a principal object of the invention to stabilize internally administered pancreatic lipase in the presence of gastric juice.
It is another object to increase the amount of active pancreatic lipase passing intact through the mammalian stomach to the intestinal tract.
It is another object to reduce the amount of exogenously provided pancreatin required to achieve an acceptable degree of relief of exocrine pancreatic insufficiency.
It is another object to provide formulated pancreatic lipase, in a dosage unit form, aiding in increasing protein and fat absorption in the mammalian gastrointestinal tract.
Lipase of pancreatic origin is generally recognized as unstable in an acid environment. The present invention provides means for substantially preventing the denaturation of this pancreatic enzyme by gastric acid, while at the same time, retaining its enzymatic activity in the intestinal environment.
According to the present invention, there is provided a method of treating exocrine pancreatic insufficiency in mammals by treating said mammals with an effective amount of a stable, solid medicinal preparation containing pancreatic lipase and Hammarsten's casein which preparation is substantially resistant to gastric disintegration. The medicament is prepared by a method which comprises:
a. intimately admixing from about 10 to about 34% lipase solid (% by weight) of finely particulated active lipase having a maximum particle size of 450 microns and preferably a maximum particle size of 150 microns and from about 66 to about 90% by weight of finely particulated Hammarsten's casein having a maximum particle size of 450 microns and preferably a maximum particle size of 150 microns;
b. a sufficient amount of a conventional water insoluble or only slightly water insoluble pharmaceutically acceptable tabletting lubricant such as stearic acid, magnesium stearate, calcium stearate and the like to facilitate tabletting of the resulting powdered medicament;
c. subjecting said medicament to tabletting in a tabletting means at a hydraulic pressure of from about 2000 to 5000 psi for a period of time sufficient to insure structural integrity on release from the press of the resulting tablet.
The results from the foregoing provide an acid-stable lipase containing medicament in tablet form having:
a. a major portion of the active lipase in finely particulated form;
b. the acid insoluble orally disintegratable Hammarsten's casein, in particulate form; and
c. a pharmaceutically acceptable tabletting lubricant in an amount sufficient to insure structural integrity of the resulting tablet during manufacture.
The acid-stable compositions of the present invention are prepared to contain from about 100 to 500 mg. of the active lipase N. F. in dosage unit form. Preferably about 200 to 250 mg. of the lipase N. F. is provided in each of the preferred tablets. It is axiomatic in this area of therapy that the exact dosage regimen will depend to a major extent on the strength of the pancreatin used. The daily dosage regimen is 400 to 2400 mg. in divided dosage, three times daily after meals.
Pancreatin is a substance containing enzymes, principally amylase, protease, and lipase, obtained from the pancreas of the hog Sus scrofa Linne var. domesticus Gray (Fam. Suidae); or of the ox, Bos taurus Linne (Fam. Bovidae).
Pancreatin N.F. converts not less than 25 times its weight of N.F. Potato Starch Reference Standard into soluble carbohydrates and not less than 25 times its weight of casein into proteoses. Pancreatin of a higher digestive power may be labeled as a whole number multiple of the two minimum activities or may be diluted by admixture with lactose or with sucrose containing not more than 3.25% of starch or with pancreatin of lower digestive power.
Pancreatin 4XNF has four times the activity of Pancreatin NF. Hammarsten's casein is casein purified by the Hammarsten method [Hammarsten, Textbook of Physiological Chemistry, 7th ed., New York, 1911, p. 619] and can be purchased from Nutrional Biochemicals Corp., Cleveland, Ohio.
The General Services Administration (GSA) method of determining pancreatic activity is based on the ability of an enzyme preparation to hydrolyze fatty acids from an emulsion of olive oil. The olive oil method is "Method B" of the General Services Administration [Interim Federal Specification P. C-0044b (GSA-FSS), Feb. 20, 1963]. The GSA activity of an enzyme is defined as the ml. of N. acid produced by 1 gram of enzyme from 1.25 ml. (1.14 g.) of olive oil at the assay pH in 2 hours at 37.degree. C. when calculated at the 5.25% level of substrate hydrolysis. Since complete alkaline saponification of 1.14 g. olive oil liberates 76.03 ml. of 0.05 N. acid, then 5.25% hydrolysis is equal to 4.00 ml. of 0.05 N. acid. ##EQU1##